Safety and Efficacy of Stand-Alone Bioactive Glass Injectable Putty or Granules in Posterior Vertebral Fusion for Adolescent Idiopathic and Non-Idiopathic Scoliosis

Posterior spinal fusion (PSF) is the standard procedure for the treatment of severe scoliosis. PSF is a standard procedure that combines posterior instrumentation with bone grafting and/or bone substitutes to enhance fusion. The aim of this retrospective study was to evaluate and compare the post-operative safety and efficiency of stand-alone bioactive glass putty and granules in posterior spine fusion for scoliosis in a paediatric cohort. A total of 43 children and adolescents were included retrospectively. Each patient’s last follow-up was performed at 24 months and included clinical and radiological evaluations. Pseudarthrosis was defined as a loss of correction measuring >10° of Cobb angle between the pre-operative and last follow-up measurements. There was no significant loss of correction between the immediate post-operative timepoint and the 24-month follow-up. There was no sign of non-union, implant displacement or rod breakage. Bioactive glass in the form of putty or granules is an easily handled biomaterial but still a newcomer on the market. This study shows that the massive use of bioactive glass in posterior fusion, when combined with proper surgical planning, hardware placement and correction, is effective in providing good clinical and radiological outcomes.


Introduction
Scoliosis is defined as three-dimensional structural deformity of the spine in the anterior-posterior, sagittal and transverse planes. The most common type is adolescent idiopathic scoliosis (AIS), but neurologic or muscular disorders may also lead to progressive spine deformities (non-idiopathic scoliosis, or NS) [1].
In the most severe cases, progression of the deformity necessitates surgery to correct the spinal curvature, rebalance the spine and, above all, stop progression [2,3]. Posterior spinal fusion (PSF) is the standard procedure for the treatment of scoliosis [4]. In paediatrics, this surgery improves self-esteem and general appearance [3]. PSF is a standard procedure that combines posterior instrumentation with bone grafting to enhance fusion [5]. Pseudoarthrosis or non-union diagnosed ≥1-year post-operatively is the main cause of fusion failure in spine surgery [4,6]. The rate of pseudarthrosis has been reported to be 0-3% with either allograft or autograft bone [4,7].
Autologous iliac crest bone grafts have long been the gold standard in posterior spine fusion [3,8,9]. However, iliac bone harvesting is associated with increased surgical time and may lead to donor site morbidity, with a risk of infection and loss of sensation or chronic pain [6,10,11]. In addition, the quantity and properties of available autologous grafts are limited. Different types of bone substitutes have been used as alternatives to autologous grafts, including allografts, ceramics, and synthetic bone substitutes [9,12]. Allografts are not free of viral contamination, and their availability is limited [10,13]. Synthetic bone substitutes have variable results but are convenient for the surgeon, easily resourced and ready to use [6].
Different bone substitutes are available on the market, but the data are limited, and no compound has yet proven to be superior to others [14]. However, 45S5 bioactive glass is an innovative biomaterial composed of optimal proportions of silicon, calcium, sodium, and phosphorus minerals. Published reports have confirmed its safety and efficacy in various adult orthopaedic conditions and procedures. The use of novel biomaterials in paediatric patients is always a concern in terms of tolerance and efficacy, particularly in posterior spinal fusion, where a large amount of graft material is needed. A study conducted by Ilharreborde et al. in 2008 [9] suggested that bioactive glass can be used in place of autologous grafts as an effective bone substitute in AIS. The safety and efficacy of bioactive glass in paediatric spinal deformities have not yet been evaluated, but there was no significant loss of correction between the 1st erect radiograph and the 24-month post-operative radiograph. There was no sign of non-union, implant displacement or rod breakage.
In our clinical practice, we routinely use bioactive glass to enhance fusion in scoliosis patients. The aim of this retrospective study was to evaluate and compare the post-operative safety and efficiency of bioactive glass 45S5 putty and granules in posterior spine fusion for AIS and NS in a paediatric cohort.

Materials and Methods
This study was conducted in accordance with the Declaration of Helsinki and the current regulations and reference methodology between July 2018 and December 2022 in a single institution. The study was approved by the Institutional Review Board CPP Ile de France 2 on 07/20/2020: No. ID RCB: 2020-A01071-38. An information letter was sent to all patients and their guardians. The present study was conducted according to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement [15].

Patient Selection
The inclusion criteria were as follows: The exclusion criteria were as follows: -surgical revision; -patient opposition to data collection.

Surgical Technique
All procedures were performed by the same surgeon. A classic straight dorsal incision, centred on the patient's spinous processes, was performed. The posterior vertebral arch was then exposed. Hybrid constructs, which combine screws, sublaminar bands and hooks, were typically used in addition to cobalt-chrome 6 mm rods. A combination of different correction manoeuvres was performed, including rod rotation, postero-medial translation and in situ contouring. A typical construct is depicted in Figure 1.
In all patients, bioactive glass in the form of GlassBone Injectable Putty or Granules (NORAKER-Lyon/France) was applied to the spine after facetectomies and standard decortication of the laminae at the end of the procedure. GlassBone Granules are composed of 45S5 bioactive glass. GlassBone putty is an injectable paste composed of 45S5 bioactive glass granules mixed with an absorbable binder combining polyethylene glycol and glycerol. The choice between putty or granules relied only on the availability of the putty on the market. Granules came first on the market and putty second. The bone harvested from the facetectomies, and the spinous processes was not used for additional grafts.

Outcomes of Interest
Baseline demographic data such as gender, age at surgery, skeletal maturity (Risser grade) and Lenke curve type were collected.
The occurrence of any anomaly and/or complication was recorded at each postoperative visit (15 days, 6 months and 2 years). Postoperative radiographs were performed at each follow-up and were evaluated for instrumentation failure, bone fusion and Cobb angle. Bone fusion in the instrumented section was classified as acquired, in progress or not acquired. Cobb angle measurement was performed at post-operative discharge and at the final follow-up visit, and the results were compared [9]. Pseudarthrosis was defined as a loss of correction manifested as a difference of >10 • between the immediate and final post-operative measurements [7,16]. As it is now accepted that loss of correction after fusion in AIS usually occurs within 2 years after the procedure [17], we used the same time interval for our study. Any screw loosening was also reported.
Pre-and post-operative radiological evaluations were performed using the EOS system (EOS-Imaging-Paris, France). EOS is a low-dose imaging system providing simultaneous AP and lateral views in a stand-up position [18,19]. Semiautomatic 3D reconstruction, using SterEOS software (EOS-Imaging-Paris, France), is based on identifiable anatomic points [20,21]. It provides a 3D image of the spine deformity, giving measurements of spine parameters in a stand-up position. The spine 3D geometry is limited between T1 and S1 since cervical spine is not routinely captured. Validation of the accuracy and reproducibility of the 3D reconstruction method has been reported in previous studies [20,22,23]: the 95% prediction limits for the intra-and inter-observer errors in measurement were computed. The 95% prediction limits indicate the difference between two successive replicate measurements that would exceed approximately 5% of the time due to an error of measurement. The inter-observer 95% prediction for the Cobb angle was 2.8 • . The intra-observer 95% predication for the Cobb angle was 2 • .

Statistical Analysis
All included patients were considered in the evaluation. A descriptive analysis of all variables of interest was performed. Ellistat (version 5.31; 2020/04, France) was used to perform t tests and other statistical tests. Continuous data are expressed as the mean and standard deviation, while categorical variables are expressed as percentages. Student's t-tests or Mann-Whitney U tests were used to compare the mean pre-and post-operative measurements. The qualitative variables are presented as counts and frequencies. The 95% confidence intervals and statistical significance are presented when relevant. The primary endpoint was the rate of adverse events at least 1 year after surgery.

Patient Selection and Demographic Data
A total of 43 children and adolescents were included retrospectively (30 females, 69.8%, and 13 males, 30.2%); their mean age at the time of surgery was 15.4 years (range 11-19 years). A flowchart of the study is presented in Figure 2. Patient demographic and clinical data are recorded in Table 1. Each patient's last follow-up was performed at 24 months after the surgery.

Safety
Four of the 43 operated patients experienced adverse events. Three complications appeared early during immediate post-operative follow-up. Two patients had surgical site infection (4.7%), which was treated with revision and cleaning, and one patient had an extended stay in the intensive care unit (2.3%). All these adverse events were due to surgical intervention. No other causes were identified. One case (2.3%) of late mechanical complications was observed 24 months after surgery. The patient was diagnosed with proximal junctional kyphosis (PJK) with dislocation of the proximal hooks; surgical revision was performed, and the instrumentation was removed. No other complications were observed during follow-up.

Radiographic Analysis
The results from the radiographic measurements are summarized in Table 3. At the latest follow-up, bony fusion was documented in all patients. The radiographic parameters of the two groups at each follow-up are presented in Table 3.

Discussion
The main finding of the present study was that bioactive glass, both in putty and in granular form, is efficient and safe to use in association with proper instrumentation, facetectomies and posterior arch decortication to enhance posterior fusion in young patients with adolescent or neuromuscular scoliosis as evaluated 2 years after surgery.
The clinical and radiological characteristics of our cohort, along with the surgical procedure and the rate of revisions and complications, are in line with the results obtained in other recent studies [9,24,25]. None of the observed patients experienced a postoperative increase in the Cobb angle by >10 • , indicating that bioglass alone is sufficient to promote fusion.
Iliac crest graft represented the gold standard for many years, but they are known to be associated with donor site morbidity [3,6,8,9,11,12]. Furthermore, the grafts may be harvested in insufficient quantity for patients requiring long fusion. At present, different synthetic options are available to surgeons, and many have proven to be as effective as iliac crest grafts [4]. These biologic materials allow solid fusion while reducing the surgical time and eliminating the donor site morbidity associated with iliac crest grafting. Ilharreborde et al. [9] reported that the use of bioactive glass in addition to local autologous bone grafts in AIS was as effective as autologous iliac crest bone alone. To the best of our knowledge, the present study is the first to show that the use of bioglass alone also represents a viable and safe option for enhancing fusion in scoliosis surgery.
While CT scans would represent the most reliable tool to evaluate the fusion mass, this imaging technique is not routinely used at our institution to limit radiation exposure [26]. Therefore, we performed an indirect evaluation of the fusion rate using the definition of pseudarthrosis suggested by Price et al. [7]. A loss of correction measuring more than 10 • of Cobb angle over the observation period was taken to define a non-fused spine [7]. The mean loss of correction was less than 2 • in our series, which is within the accepted 3 • measurement error (Figure 4). The need for a safety evaluation of the massive use of bioglass on the spine is evident from the issues experienced with high doses of bone morphogenetic proteins (BMPs) in spine surgery [27]. Bioactive glass is an osteoconductive bone substitute and not an osteoinductive agent as BMP is, meaning that bioglass merely acts as a scaffold to promote the settlement of osteoblasts arising from bone decortication. BMPs create bone in a bonefree environment and have a well-documented dose effect. As safety is a priority and a legitimate concern when applying newly developed biomaterials in the human body, we kept this concern in mind and examined safety as an outcome of this study. In the cohort that we observed, bioactive glass did not have the disadvantage of a dose effect. At least 20 cc of bioactive glass was applied in most of the patients without adverse effects. While a longer follow-up will be required to investigate possible long-term effects, we believe that, to the osteoconductive rather than osteoinductive nature of bioglass, there will not be long-term complications associated with the use of this material.
In studies on oral microorganisms in vitro, bioglass has demonstrated antibacterial properties, which may reduce the potential for bacterial colonization of the grafted sites [28,29]. The 4.7% infection rate in our study is equivalent to the values reported in the recent literature. Both patients who developed wound infections in this study were NS patients, and people with this condition are known to be more prone to infections than people with AIS. We were unable to evaluate the antibacterial properties owing to the design of the study and the small sample of patients, and we did not detect a trend in the rate of operating site infections in our patients to support these properties. However, in light of our data compared with the literature, it is highly unlikely that the observed wound infections were connected to the use of bioglass.
We did not observe a significant difference in outcomes between patients who received putty grafts and those who received granular grafts. The bioactive glass putty plays the same role as granules. There are no primary mechanical properties to consider when applying bioactive glass putty. This is not an issue in posterior spinal fusion because the instrumentation assures primary mechanical stabilization, but a putty graft may not be a suitable stand-alone solution for bone filling. However, the "wet sand" consistency and adhesive properties facilitate the accurate placement of the biomaterial. Once applied to the bone, it does not move, even in the event of irrigation or bleeding. It is also very useful in intersomatic cages. Hammering a cage during insertion does not dislodge the putty from the cage, as is usually experienced when small autologous bone fragments are used instead. For those reasons, bioactive glass putty has progressively replaced granules in most spine procedures.
The retrospective nature and uncontrolled design of this study are its main limitations. While these observations confirmed the efficacy and safety of stand-alone bioactive glass 45S5 as an alternative to autologous bone grafts, further studies will be required to compare the available materials and assess possible differences among the various compounds.

Conclusions
PSF is currently a common procedure that has a very low rate of complications, regardless of the type of biomaterial used. Bioactive glass in the form of putty or granules is an easily handled biomaterial but still a newcomer on the market. This study shows that its massive use in posterior fusion, when combined with proper surgical planning, hardware placement and correction, is effective in providing good clinical and radiological outcomes.  Informed Consent Statement: Informed consent was obtained from all subjects involved in the study. Written informed consent was obtained from the patient and/or parents to publish this paper. Data Availability Statement: Data available on request to corresponding author.